QUESTIONS What are the effects of interventions to reduce symptoms of acute infective sore throat?... 3

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1 Search date September 213 Tim Kenealy ABSTRACT INTRODUCTION: About 1% of people present to primary healthcare services with sore throat each year. The causative organisms of sore throat may be bacteria (most commonly Streptococcus) or viruses (typically rhinovirus), although it is difficult to distinguish bacterial from viral infections clinically. METHODS AND OUTCOMES: We conducted a systematic and aimed to answer the following clinical question: What are the effects of interventions to reduce symptoms of acute infective sore throat? We searched Medline, Embase, The Cochrane Library, and other important databases up to September 213 (Clinical Evidence s are updated periodically; please check our website for the most uptodate version of this ). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 6 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic, we present information relating to the effectiveness and safety of the following interventions: antibiotics, corticosteroids, nonsteroidal antiinflammatory drugs, and paracetamol. QUESTIONS What are the effects of interventions to reduce symptoms of acute infective sore throat? TREATING SYMPTOMS Likely to be beneficial Paracetamol (acetaminophen) Corticosteroids (in people receiving antibiotics) Trade off between benefits and harms NSAIDs Antibiotics INTERVENTIONS Covered elsewhere in Clinical Evidence Acute bronchitis Acute otitis media Acute sinusitis Common cold Tonsillitis Key points is an acute upper respiratory tract infection that affects the respiratory mucosa of the throat. About 1% of people in Australia present to primary healthcare services with sore throat each year. The causative organisms of sore throat may be bacteria (most commonly Streptococcus) or viruses (typically rhinovirus), but it is difficult to distinguish bacterial from viral infections clinically. Paracetamol seems to effectively reduce the pain of acute infective sore throat after regular doses over 2 days. There is a risk of rare but serious skin reactions with paracetamol (acetaminophen). Nonsteroidal antiinflammatory drugs (NSAIDs) may reduce the pain of sore throat at 2 to 5 days. NSAIDs are associated with gastrointestinal and renal adverse effects. Antibiotics can reduce the proportion of people with symptoms associated with sore throat at 3 days. Reduction in symptoms seems greater for people with positive throat swabs for Streptococcus than for people with negative swabs. Antibiotics are generally associated with adverse effects such as nausea, rash, vaginitis, and headache, and widespread use may lead to bacterial resistance. Corticosteroids added to antibiotics may reduce the severity of pain from sore throat in people compared with antibiotics alone. Most trials used a single dose of corticosteroid. However, data from other disorders suggest that longterm use of corticosteroids is associated with serious adverse effects. DEFINITION is an acute upper respiratory tract infection that affects the respiratory mucosa of the throat. Since infections can affect any part of the mucosa, it is often arbitrary whether an acute upper respiratory tract infection is called 'sore throat' ('pharyngitis' or 'tonsillitis'), 'common cold', 'sinusitis', 'otitis media', or 'bronchitis' (see figure 1, p 9 ). Sometimes, all areas are affected (simultaneously or at different times) in one illness. In this, we aim to cover people whose principal presenting symptom is sore throat. This may be associated with headache, fever, and general malaise. Suppurative complications include acute otitis media (most commonly), acute sinusitis, and peritonsillar abscess (quinsy). Nonsuppurative complications include acute rheumatic fever and acute glomerulonephritis.this does not include people with previous rheumatic fever or previous glomerulonephritis, who are importantly different from the general population of BMJ Publishing Group Ltd 214. All rights reserved Clinical Evidence 214;3:159

2 INCIDENCE/ PREVALENCE people with sore throats. It also does not include people who are clinically seriously unwell (as these people are typically not included in the primary studies). There is little seasonal fluctuation in sore throat. About 1% of the Australian population present to primary healthcare services annually with an upper respiratory tract infection consisting predominantly of sore throat. [1] This reflects about one fifth of the overall annual incidence. [1] However, it is difficult to distinguish between the different types of upper respiratory tract infection. [2] A Scottish mail survey found that 31% of adult respondents reported a severe sore throat in the previous year, for which 38% of these people visited a doctor. [3] AETIOLOGY/ The causative organisms of sore throat may be bacteria (Streptococcus, most commonly group A RISK FACTORS betahaemolytic, but sometimes Haemophilus influenzae, Moraxella catarrhalis, and others) or viruses (typically rhinovirus, but also coronavirus, respiratory syncytial virus, metapneumovirus, Epstein Barr virus, and others). It is difficult to distinguish bacterial from viral infections clinically. Features suggestive of Streptococcus infection are: fever >38.5 C, exudate on the tonsils, anterior neck lymphadenopathy, and absence of cough. [4] can be caused by processes other than primary infections, including GORD, physical or chemical irritation (e.g., from nasogastric tubes or smoke), and occasionally hay fever. However, we consider only primary infections in this. PROGNOSIS The untreated symptoms of sore throat disappear by 3 days in about 4% of people, and untreated fevers in about 85%. By 1 week, 85% of people are symptomfree. This natural history is similar in Streptococcuspositive, Streptococcusnegative, and untested people. AIMS OF To relieve symptoms of sore throat for 48 hours or longer. INTERVENTION OUTCOMES : reduction in severity and duration of symptoms (sore throat pain, general malaise, headache, and fever) assessed at 48 hours or longer; patient satisfaction; health care utilisation. Time off work or school. of treatment. METHODS Clinical Evidence search and appraisal September 213. The following databases were used to identify studies for this systematic : Medline 1966 to September 213, Embase 198 to September 213, and The Cochrane Database of Reviews 213, issue 9 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of s (DARE) and the Health Technology Assessment (HTA) Database. We also searched for retractions of studies included in the. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the were then extracted by an evidence analyst. Study design criteria for inclusion in this were published systematic s and RCTs. Open label trials were included where outcomes were objective; for subjective outcomes, trials were at least singleblinded and containing 2 or more individuals, of whom more than 8% were followed up. There was a minimum length of followup of 48 hours. We included RCT and systematic s of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the s as required. To aid readability of the numerical data in our s, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this (see table, p 1 ). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website ( BMJ Publishing Group Ltd 214. All rights reserved

3 QUESTION OPTION What are the effects of interventions to reduce symptoms of acute infective sore throat? PARACETAMOL (ACETAMINOPHEN) TO REDUCE SYMPTOMS OF ACUTE INFECTIVE SORE THROAT For GRADE evaluation of interventions for, see table, p 1. Paracetamol seems to effectively reduce the pain of acute infective sore throat after regular doses over 2 days. The FDA issued a drug safety alert on the risk of rare but serious skin reactions with paracetamol (acetaminophen) (August 213). Benefits and harms Paracetamol versus placebo: We found one systematic (search date 1999, 3 RCTs, 312 people with acute moderate to severe sore throat for up to 4 days) [6] comparing paracetamol (acetaminophen) versus placebo. Two RCTs (158 people) identified by the assessed the effects of paracetamol over 24 hours or less, and so we have not reported these data further. Paracetamol compared with placebo Paracetamol seems more effective than placebo at reducing sore throat pain at 2 days (lowquality evidence). [6] 154 children pain, 2 days 34% greater reduction with Data from 1 RCT with paracetamol 3 times daily paracetamol than with placebo with placebo P <.1 paracetamol 3 times daily No data from the following reference on this outcome. [6] Further information on studies Comment: Drug safety alert August 213, paracetamol (acetaminophen) The Food and Drug Administration (FDA) has issued a drug safety alert on the risk of rare but serious skin reactions with paracetamol (acetaminophen). These skin reactions, known as StevensJohnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalised exanthematous pustulosis (AGEP), can be fatal.( OPTION NSAIDS TO REDUCE SYMPTOMS OF ACUTE INFECTIVE SORE THROAT For GRADE evaluation of interventions for, see table, p 1. NSAIDs may reduce the pain of sore throat at 2 to 5 days. NSAIDs are associated with gastrointestinal and renal adverse effects. BMJ Publishing Group Ltd 214. All rights reserved.... 3

4 Benefits and harms NSAIDs versus placebo: We found one systematic (search date 1999, 12 RCTs, 1189 people with acute sore throat for up to 5 days, severity unclear) [6] and one subsequent RCT [7] comparing NSAIDs versus placebo. The did not perform a meta. Seven RCTs (492 people) identified by the assessed the effects of NSAIDs (including 1 RCT of oral aspirin and 1 RCT of aspirin gum) over 24 hours or less, and so we have not reported these data further. Six RCTs (697 people) identified by the assessed the effects of NSAIDs over 24 hours and above. NSAIDs compared with placebo NSAIDs may be more effective than placebo at reducing sore throat symptoms at 2 to 5 days (lowquality evidence). [6] 697 people 6 RCTs in this, primarily throat pain, 2 to 5 days with NSAIDs with placebo Pain was assessed using a variety of visual analogue and scoring systems All the RCTs found that NSAIDs significantly reduced symptoms (primarily throat pain) compared with placebo The range of significant improvements in symptoms compared with placebo ranged from 33% to 93% P <.5 in all RCTs NSAIDs [7] RCT 373 adults aged 18 to 75 years with recentonset sore Reduction in difficulty swallowing, at day 2 throat (4 days or with flurbiprofen (n = 186) less) with placebo (n = 187) P =.16 flurbiprofen Both groups had paracetamol for the home management of pain during these 2 days [7] RCT 373 adults aged 18 to 75 years with recentonset sore Reduction in difficulty swallowing, at day 3 throat (4 days or with flurbiprofen (n = 186) less) with placebo (n = 187) P =.32 flurbiprofen Both groups had paracetamol for the home management of pain during these 2 days [7] RCT 373 adults aged 18 to 75 years with recentonset sore throat (4 days or less) Patient satisfaction (felt less distracted, felt less frustrated, felt happier), at day 3 with flurbiprofen (n = 186) with placebo (n = 187) P <.5 flurbiprofen Both groups had paracetamol for the home management of pain during these 2 days BMJ Publishing Group Ltd 214. All rights reserved.... 4

5 [7] RCT [7] RCT 373 adults aged 18 to 75 years with recentonset sore throat (lessthan or equal to4 days) 373 adults aged 18 to 75 years with recentonset sore throat (lessthan or equal to4 days) Serious adverse events, at day 3 /186 (%) with flurbiprofen /187 (%) with placebo Gastrointestinal adverse events, at day 3 9/186 (4.8%) with flurbiprofen 8/187 (4.3%) with placebo No data from the following reference on this outcome. [6] Further information on studies [6] Significance assessment not reported Significance assessment not reported The gave no information on adverse effects. However, data from systematic s in people with other disorders suggest that NSAIDs are associated with gastrointestinal and renal adverse effects (see on NSAIDs). Comment: Clinical guide: NSAIDs seem effective, but have potential for adverse effects. Aspirin is best avoided in children <15 years of age owing to the rare risk of Reye's syndrome. OPTION ANTIBIOTICS TO REDUCE SYMPTOMS OF ACUTE INFECTIVE SORE THROAT For GRADE evaluation of interventions for, see table, p 1. Antibiotics can reduce the proportion of people with symptoms associated with sore throat at 3 days. Reduction in symptoms seems greater for people with positive throat swabs for Streptococcus than for people with negative swabs. Antibiotics are generally associated with adverse effects such as nausea, rash, vaginitis, and headache, and widespread use may lead to bacterial resistance. Benefits and harms Antibiotics versus placebo: We found one systematic (search date 28, 27 randomised or quasirandomised trials, 12,835 people with sore throat, severity unclear) comparing antibiotics versus placebo. Antibiotics compared with placebo Antibiotics are more effective than placebo at reducing sore throat and headache at 3 days, particularly in people with positive throat swabs for Streptococcus (moderatequality evidence) people, 3 days RR RCTs in this 16/266 (49%) with antibiotics 131/1555 (66%) with placebo 95% CI.59 to.79 antibiotics BMJ Publishing Group Ltd 214. All rights reserved.... 5

6 2974 people 13 RCTs in this 1334 people 7 RCTs in this 911 people 3 RCTs in this, 6 to 8 days 246/1839 (13%) with antibiotics 26/1135 (18%) with placebo Fever, 3 days with antibiotics with placebo Headache, 3 days 122/552 (22%) with antibiotics 147/359 (41%) with placebo RR.49 95% CI.32 to.76 The estimated that this represents an average shortening of symptoms of sore throat by about 16 hours for the first week RR.71 95% CI.45 to 1.1 RR.47 95% CI.38 to.58 antibiotics Not significant antibiotics No data from the following reference on this outcome. Further information on studies Severely unwell people were not included in the RCTs included in the systematic. Consequently, these findings may not apply to those people. The found limited evidence from indirect comparisons that, in people with throat swabs positive for Streptococcus, the absolute and relative reduction in the proportion of people with sore throat symptoms at 3 days was greater than in people with negative swabs (positive swabs: 11 trials, 471/173 [44%] with antibiotics v 544/766 [71%] with placebo, RR.58, 95% CI.48 to.71; negative swabs: 6 trials, 262/458 [57%] with antibiotics v 22/278 [73%] with placebo, RR.78, 95% CI.63 to.97). The gave no information about the adverse effects associated with antibiotic use. However, data from systematic s in people with other disorders suggested that antibiotics were associated with nausea, vomiting, headache, skin rash, and vaginitis (see s on Acute bronchitis and Acute otitis media in children). Comment: Clinical guide: Widespread antibiotic use may lead to bacterial resistance to antibiotics (see on Acute bronchitis). OPTION CORTICOSTEROIDS TO REDUCE SYMPTOMS OF ACUTE INFECTIVE SORE THROAT..... For GRADE evaluation of interventions for, see table, p 1. Corticosteroids added to antibiotics may reduce the severity of pain from sore throat in people compared with antibiotics alone. There is insufficient evidence to report separately on children. Most trials used a single dose. However, data from use of corticosteroids in other disorders suggest that longterm use of corticosteroids is associated with serious adverse effects. BMJ Publishing Group Ltd 214. All rights reserved.... 6

7 Benefits and harms Corticosteroids versus placebo in people receiving antibiotics: We found one systematic (search date 212, 8 RCTs, 743 people [369 children, 374 adults], of whom 47% had exudative sore throat and 44% were positive for group A betahaemolytic streptococcus) comparing corticosteroids versus placebo. [8] In seven RCTs, all participants also received antibiotics; in one RCT, participants received antibiotics if direct antigen testing for Streptococcus was positive. The corticosteroids used were dexamethasone orally or intramuscularly (single dose, 6 RCTs), betamethasone intramuscularly (single dose, 1 RCT), or prednisone orally (1 2 days, 1 RCT). Two RCTs included only children, two included only adults, and four included both. The systematic pooled the data on adults and children and did not present the results separately by age. Four RCTs (286 adults and children) identified by the assessed the effects of corticosteroids at 24 hours, and so we have not reported these data further. Corticosteroids compared with placebo in people receiving antibiotics Dexamethasone, betamethasone, or prednisone (single dose or for 1 2 days), with concurrent antibiotic, are more effective than placebo at complete resolution of pain in people with sore throat at 48 hours (moderatequality evidence). [8] 29 adults and children 3 RCTs in this Complete resolution of pain, 48 hours 74/98 (75%) with oral or intramuscular corticosteroids 52/111 (47%) with placebo RR % CI 1.32 to 2.6 NNT 3 95% CI 2 to 6 corticosteroids Time off work or school Corticosteroids compared with placebo in people receiving antibiotics We don't know whether corticosteroids are more effective than placebo at reducing time off work or school (lowquality evidence). Time off work or school [8] 92 people Data from 1 RCT Number of days off work or school, mean.4 with corticosteroids (n = 46) MD.3 95% CI.87 to +.27 Not significant.7 with placebo (n = 46) [8] At least 125 participants 4 RCTs in this with See Further information on studies Further information on studies [8] The SR noted that adverse events were reported in detail by only one RCT of 125 participants, in which five participants (three corticosteroid and two placebo) were hospitalised for fluid rehydration and three participants BMJ Publishing Group Ltd 214. All rights reserved.... 7

8 (one corticosteroid and two placebo) developed peritonsillar abscesses. One RCT reported no side effects attributable to dexamethasone; another did not identify any complications of Group A betahaemolytic streptococcus infections in either group; and, in a third RCT, there were no participants with additional complaints or requiring additional medications. Comment: Clinical guide: A single dose of corticosteroid seems to reduce pain earlier than placebo in people with or without evidence of streptococcal infection. There is insufficient evidence to report separately on children. GLOSSARY Lowquality evidence Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Moderatequality evidence Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. SUBSTANTIVE CHANGES Corticosteroids to reduce symptoms of acute infective sore throat Existing updated. [8] Existing evidence reassessed. Categorisation unchanged (likely to be beneficial). NSAIDs to reduce symptoms of acute infective sore throat One RCT added. [7] Categorisation unchanged (tradeoff between benefits and harms). Paracetamol (acetaminophen) to reduce symptoms of acute infective sore throat Evidence reassessed. One RCT deleted, as it no longer fits the new stricter inclusion criteria for this Clinical Evidence. Categorisation unchanged (likely to be beneficial). REFERENCES 1. Del Mar C, Pincus D. Incidence patterns of respiratory illness in Queensland estimated from sentinel general practice. Aust Fam Physician 1995;24: ,632.[PubMed] 2. Benediktsdóttir B. Upper airway infections in preschool children frequency and risk factors. Scand J Prim Health Care 1993;11: [PubMed] 3. Hannaford PC, Simpson JA, Bisset AF, et al. The prevalence of ear, nose and throat problems in the community: results from a national crosssectional postal survey in Scotland. Fam Pract 25;22: [PubMed] 4. Dagnelie CF, Bartelink ML, van der Graaf Y, et al. Towards a better diagnosis of throat infections (with group A betahemolytic streptococcus) in general practice. Br J Gen Pract 1998;48: [PubMed] 5. Del Mar CB, Glasziou PP, Spinks AB. Antibiotics for sore throat. In:The Cochrane Library, Issue 9, 213. Chichester, UK: John Wiley & Sons, Ltd. Search date Thomas M, Del Mar C, Glaziou P. How effective are treatments other than antibiotics for acute sore throat? Br J Gen Pract 2;5: [PubMed] 7. Russo M, Bloch M, de Looze F, et al. Flurbiprofen microgranules for relief of sore throat: a randomised, doubleblind trial. Br J Gen Pract 213;63:e149 e155.[pubmed] 8. Hayward G, Thompson MJ, Perera R, et al. Corticosteroids as standalone or addon treatment for sore throat. In: The Cochrane Library, Issue 1, 212. Chichester, UK: John Wiley & Sons, Ltd. Search date 212. Tim Kenealy Associate Professor Department of General Practice and Primary Health Care University of Auckland Auckland New Zealand Competing interests: TK declares that he has no competing interests. We would like to acknowledge the previous contributors for this, including Chris Del Mar and Paul Glasziou. BMJ Publishing Group Ltd 214. All rights reserved.... 8

9 FIGURE 1 Confusion and overlap in the classification of acute respiratory infections. Disclaimer The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication. BMJ Publishing Group Ltd 214. All rights reserved.... 9

10 GRADE Important outcomes Studies (Participants) Evaluation of interventions for. Outcome Comparison Type of evidence What are the effects of interventions to reduce symptoms of acute infective sore throat? 1 (154) [6] Paracetamol versus 4 placebo [6] [7] 7 (17) 27 (12,835) 3 (29) [8] 1 (92) [8] Time off work or school NSAIDs versus placebo Antibiotics versus placebo Corticosteroids versus placebo in people receiving antibiotics Corticosteroids versus placebo in people receiving antibiotics ,, Time off work or school Quality Consistency Directness GRADE Low Low Moderate Moderate Low Comment Quality points deducted for incomplete reporting of results and sparse data Quality point deducted for incomplete reporting of results; directness point deducted for inclusion of a cointervention Directness point deducted for narrow inclusion criteria Directness point deducted for population differences between studies Quality points deducted for sparse data and incomplete results We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasirandomisation, sparse data [<2 people in the ]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. : based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio. BMJ Publishing Group Ltd 214. All rights reserved